Transformed protein Ras is involved in the proliferation of cancer cells. The Ras must be farnesylated before this proliferation can occur. Farnesylation of Ras by farnesyl pyrophosphate (FPP) is effected by protein farnesyltransferase. Inhibition of protein farnesyltransferase and, thereby, of farnesylation of the Ras protein, blocks the ability of transformed cells to proliferate.
Activation of Ras also partially mediates smooth muscle cell proliferation (Circulation, I-3:88 (1993). Inhibition of protein farnesyltransferase and, thereby, of farnesylation of the Ras protein, will aid in the prevention of restenosis.
The compounds of the invention are also inhibitors of squalene synthase. Squalene synthase is a microsomal enzyme which catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate (FPP) in the presence of nicotinamide adenine dinucleotide phosphate, reduced form, (NADPH) to form squalene (Poulter, C. D., Rilling, H. C., in "Biosynthesis of Isoprenoid Compounds", Vol. I, Chapter 8, pp. 413-441, J. Wiley and Sons, 1981 and references therein). This enzyme is the first committed step of the de novo chlolesterol biosynthetic pathway. Thus inhibitors of squalene synthase cause inhibition of cholesterol biosynthesis and thus act as a hypocholesterolemic agents. Thus squalene synthase inhibitors are useful for the treatment and prevention of hyperlipidemia or atherosclerosis or other disorders resulting from an excess of cholesterol.
Inhibition of squalene synthase also results in the inhibition of fungal growth.